Children with Neutrophil-Predominant Severe Asthma Have Proinflammatory Neutrophils With Enhanced Survival and Impaired Clearance

• Type of Material: Article
• Authors: Jocelyn Grunwell, Emory University; Susan T. Stephenson, Emory University; Rabindra Tirouvanziam, Emory University; Louann Brown, Emory University; Milton Brown, Emory University; Anne Fitzpatrick, Emory University
• Language: English
• Date: 2019-02-01
• Publisher: Elsevier Science BV.
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 American Academy of Allergy, Asthma & Immunology
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.jaip.2018.08.024
• Title of Journal or Parent Work: Journal of Allergy and Clinical Immunology: In Practice
• Volume: 7
• Issue: 2
• Start Page: 516
• End Page: +
• Grant/Funding Information: None declared
• Keywords: Pediatric severe asthma; Differential gene-expression; Inflammation; Asthma phenotype; Life Sciences & Biomedicine; Severe asthma; Asthma endotype; Allergy; Eosinophils; Airway macrophage; Immunology; Non-type 2 inflammation; Sputum; Heterogeneity; Respiratory burst; Healthy adults; Neutrophil activation; Identification; Phagocytosis; Relevant; Neutrophil extracellular trap; Phenotype; Pediatric patients with asthma; Science & Technology; Reveals
• Research Categories: Biology, Genetics; Health Sciences, Immunology; Health Sciences, Human Development

Abstract

Background: Airway neutrophils are abundant in some children with severe asthma, but their functions are poorly understood. Objective: To characterize that the inflammatory airway environment of children with neutrophil-predominant severe asthma promotes neutrophil survival and disrupts neutrophil-associated innate immune defenses. Methods: Sixty-seven children with severe asthma refractory to high-dose inhaled corticosteroid treatment undergoing bronchoscopy with bronchoalveolar lavage (BAL) for clinical indications were stratified into neutrophil “high” versus “low” groups on the basis of BAL differential counts. Neutrophil activation markers, functional assays, and phenotyping studies were performed, as well as airway macrophage functional assays. Results were compared with those from children with moderate asthma treated with inhaled corticosteroids. Results: Children with neutrophil-predominant severe asthma had increased markers of neutrophil activation/degranulation and a greater magnitude of airway proinflammatory cytokine and chemokine release. Primary neutrophils exposed to BAL of these children exhibited greater phagocytic capability and greater neutrophil extracellular trap formation, but a more impaired respiratory burst. Despite greater abundance of airway TGF-β1, the neutrophils were not more apoptotic. Instead, neutrophils had a highly proinflammatory phenotype associated with a number of surface markers that regulate neutrophil activation, recruitment/migration, and granule release. Airway macrophages from children with neutrophil-predominant severe asthma were also more proinflammatory with impaired phagocytosis and increased apoptosis. Conclusions: Children with neutrophil-predominant severe asthma have proinflammatory neutrophils with enhanced survival. Airway macrophages are also proinflammatory and dysfunctional and may contribute to global innate immune impairment. Therapies that target neutrophils and related inflammation may be warranted in this subset of children.